This invention relates to vitamin D compounds, and more particularly to 6-methylvitamin D3 analogs and their pharmaceutical uses.
The most active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 is a potent calcium and phosphorous-regulating hormone playing an important role in bone homeostasis in animals and humans. Also, in addition to this classical role, the natural hormone elicits immunomodulation as well as cell differentiation and proliferation activities in numerous malignant cells and keratinocytes [Feldman et al, Vitamin D, 2nd ed.; Elsevier Academic Press: New York, 2005]. 1α,25-Dihydroxyvitamin D3 expresses these functions by binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. Structural analogs of this metabolite have been prepared and tested such as 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, and various other side-chain and A-ring modified vitamins. Some potent synthetic analogs have been used clinically to treat bone disorders such as osteoporosis and the skin disorder—psoriasis. Some of these compounds exhibit separation of activities in cell differentiation and calcium regulation. The difference in activity may be advantageous in treating a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and other malignancies.
Although more than 3000 synthetic analogs of the natural hormone have been obtained and tested to date, very few of them were characterized by substitution of the intercyclic C(5)=C(6)-C(7)=C(8) diene moiety. 6-Fluorovitamin D3 was synthesized by Dauben et al. [J. Org. Chem. 50, 2007 (1985)] and this compound has been shown to antagonize 1α,25-(OH)2D3 activity, especially intestinal calcium absorption, in vivo in chicken [Wilhelm et al., Arch. Biochem. Biophys. 233, 127 (1984)]. The synthesis of 6-methylvitamin D3 was reported by Sheves and Mazur [J. Chem. Soc., Chem. Commun. 21 (1977)] using 6-oxo-3,5-cyclovitamin D precursor; the same compound was also obtained by Yamada et al. [Tetrahedron Letters 22, 3085 (1981)] by reductive thermal desulfonylation of the 6-methylated vitamin D3-sulfur dioxide adduct. Recently, 1α-hydroxy-6-methylvitamin D3 was synthesized by a novel approach involving Pd-catalyzed carbocyclization—Negishi cross-coupling cascade [Reino et al., Org. Lett. 7, 5885 (2005)].
Compounds alkylated at C-6 seemed to be interesting targets for synthetic and biological studies. Such vitamin D analogs easily undergo thermal conversion to their previtamin forms. Moreover, the results of molecular modeling indicate that significant deviation from planarity must be present in their diene system, connecting the ring A to the C,D-hydrindane fragment. This is obviously associated with the interaction of the 6-alkyl substituent and hydrogens from the C-ring (at C-9). Such deviation from the planar geometry can be of importance when the vitamin D analog forms a complex with VDR. Recently, Moras et al. reported the X-ray crystal structure of the ligand binding domain (LBD) of the hVDR complexed with the native hormone [Moll. Cell, 5, 173 (2000)]. Later, many other crystal structures of the LBD-VDR bound to different vitamin D compounds were solved and it became clear that VDR binds (at least in the crystalline state) the vitamin D ligands having their intercyclic C(5)=C(6)-C(7)=C(8) diene moiety in the s-trans conformation, exhibiting a torsion angle of ca. −150°. Therefore, in a continuing effort to develop 1α,25-dihydroxyvitamin D3 analogs with biological profiles suitable for pharmaceutical uses we have synthesized 6-methyl analog of 1α,25-dihydroxyvitamin D3.